Vical Inc. seeks SBIR Phase II funding to develop and produce a licensable prophylactic anthrax vaccine. This project will move on an accelerated but realistic timeline with plans for human clinical trials to begin in September 2003. Although many candidate vaccines are being studied for anthrax prevention or post-exposure prophylaxis, the Vical approach has a number of advantages. First, we are finishing the preclinical work needed, and will approach the FDA for a pre-IND meeting to be held in March 2003. Second, DNA vaccines studied to date have been very safe in humans. Third, these vaccines have the potential for long-term stability and storage. Fourth, we are achieving antibody titers that are consistent with the levels needed for protection. Fifth, our vaccine may induce greater T cell help and memory than planned recombinant protein vaccines. Sixth, the Vical vaccine will focus on two gene products (PA plus LF) rather than PA alone, which may induce broader protection. The vaccine development plan will follow a logical series of experiments in mice, rabbits, cynomologus monkeys, and humans. In Aim 1 we will determine the final vaccine formulation that will proceed to human trials. Present experiments funded by a Phase I STTR will provide the data for choosing a final 2 formulations and constructs from among our many candidate vaccines. Cynomologus immunogenicity studies will then be performed with these candidates to determine which combination induces the optimal antibody titers. Rabbit studies will also be performed to better define the length of protection induced by our vaccines. In Aim 2 we will move a final single formulation forward into human clinical trials. This will be accomplished by conducting the appropriate quality control, toxicology and safety studies of the GMP produced vaccine, and by filing the appropriate regulatory paperwork for an IND with the FDA. The human clinical phase I trial will be a dose-ranging, open-label safety study. In Aim 3 we will select a dose from our phase I studies needed to perform a sufficiently powered clinical trial to establish vaccine safety in humans. We will also conduct the necessary studies in non-human primates to demonstrate protection from an aerosolized B. anthracis challenge using the same vaccine studied in humans. We will also collect sufficient antibody through plasmapheresis of the human subjects during our clinical trials to be able to perform passive transfer experiments in the cynomologus monkeys. These final studies will better define the role of antibody in the expected immunity to challenge.